Abstract Three major academic centers propose to collaborate as a combined clinical-technology site. The 2 clinical centers, NYU and Einstein, have a rich and long history of commitment to SLE and together currently treat ~1,000 SLE patients. They will jointly assemble a renal phenotype-driven patient cohort comprising diverse ethnic/racial backgrounds. The Multi-Ethnic Translational Research Optimization (METRO) Lupus Consortium cohort will be leveraged to develop, standardize and validate advanced technologies to identify critical signaling pathways in tissues (renal and skin), cells and urine. Given the widespread vasculopathy characteristic of SLE, endothelial cell activation in the tubulointerstitium in lupus nephritis (LN) may be accompanied by similar activation, even in non-lesional skin. Gene expression and signaling in specific subsets of renal cells may precede and predict the pathologic processes that lead to end organ damage and provide insights to deconstruct the heterogeneity of lupus in general, and the histologic class of renal disease in particular. Furthermore, the faithful reflection of a relevant pathway in renal tissue by a more readily accessible tissue or fluid compartment would pave the way to early identification and treatment, critical to renal survival. Because SLE is strongly associated with racial/ethnic disparities, studies need to address whether specific biological pathways and drug targets are race/ethnicity dependent. Accordingly, METRO will comprise substantial numbers of Black, Hispanic, Asian, and White patients recruited at NYU (PI Buyon) and Einstein (PI Putterman). PI Dr. Thomas Tuschl at The Rockefeller University brings expertise and extensive experience in coding and non-coding RNA-seq analysis and RNA diagnostic and therapeutic development. The proposal addresses 2 objectives: i) identification of candidate targets to guide novel therapy; and ii) development of non-invasive strategies to maximize early detection of LN. The former will be approached by identifying unique patterns from single-cell analysis (including RNA deregulation or mutation/allelic variation) in LN kidney cells (including capillary endothelial cells) compared with normal tissue/cells, and the latter by similar RNA analysis in LN matched with non-lesional skin, PBMC, and urine cellular pellet (UCP). Operationally the project is approached in sequential phases: Aim 1 (Phase 0, UH2): To establish the optimal method of renal tissue collection and single cell isolation of resident and infiltrating cells followed by polyA RNAseq, and similar application to cell populations present in non-lesional skin, PBMC, and UCP. Aim 2 (Phase I, UH2): To identify RNA-seq patterns associated with different biopsy classes and compare with non- lesional skin (endothelial cells), PBMC, and UCP from the same patient. Aim 3 (Phase II, UH3): To establish whether a) the renal tissue RNA-seq pattern associates with biopsy class, activity, and chronicity segregated by race/ethnicity; b) renal pattern tracks response to therapy and/or progression of renal disease in new onset or recurrent disease; and c) the pattern in skin, PBMC or UCP antedates new or relapsing kidney involvement.